Gonadotropin Releasing Hormone (GnRH, or it is also called Luteinizing Hormone Releasing Hormone: LHRH, hereinafter referred to as “GnRH”) is a peptide consisting of 10 amino acids: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), which is secreted from the hypothalamus. GnRH secreted into hypophyseal portal vein promotes the production and secretion of gonadotropin of anterior pituitary hormones, Luteinizing Hormone: LH and Follicle Stimulating Hormone: FSH, via the receptors which are considered to exist in the anterior lobe of the pituitary, GnRH receptor. These gonadotropins affect gonad, ovary and testis, to promote the follicular growth, ovulation and luteinization and spermatogenesis and also promote the production and secretion of sex hormones such as estrogen, progesterone and androgen (see Non-patent reference 1). Accordingly, antagonists specifically and selectively acting on the GnRH receptors should control the activities of GnRH and control the production and secretion of gonadotropin and sex hormones, and therefore, are expected to be useful as an agent for the prevention or treatment of sex hormone-dependent diseases.
As an agent inhibiting the function of GnRH receptor, GnRH receptor superagonists (hereinafter referred to as “GnRH superagonist”) have been used as agents for the treatment of sex hormone-dependent diseases such as pro static cancer, breast cancer, endometriosis and the like. The GnRH superagonists bind GnRH receptors and exert an initial temporary gonadotropin secretion-stimulating effect so-called “flare-up phenomenon”, and then suppress the function by causing gonadotropin depletion and GnRH receptor down-regulation to suppress. Therefore, the GnRH receptor superagonists have a problem that the disease becomes exacerbated transiently by the initially promoted secretion of gonadotropin. On the other hand, the suppression mechanism of GnRH receptor antagonists (hereinafter referred to as “GnRH antagonist”) is an inhibition of the binding to GnRH receptors, and therefore, are expected to exert promptly suppressive effects without secretion of gonadotropin. In these years, as GnRH antagonists, peptidic GnRH antagonists such as abarelix and cetrorelix have been developed and used for the treatment of prostatic cancer, infertility and the like. However, since these peptidic GnRH antagonists have bad oral absorbability, they have to be subcutaneously or intramuscularly administered. Thus, development of a non-peptidic GnRH antagonist which can be orally administered wherein local reactivity at injected sites can be reduced and the dosages can be flexibly adjusted is desired (see Non-patent reference 2).
As fused pyrimidine derivatives having a non-peptidic GnRH antagonistic activity, compounds described in Patent references 1 and 2 and the like are known. However, all compounds described in Patent reference 1 have an aryl substituent on the 5-membered hetero ring fused with a pyrimidine ring. In addition, compounds described in Patent reference 2 are pyrimidine derivatives fused with a 6-membered aromatic ring and their oral absorbability is necessarily high. In Patent reference 3 recently published, pyrimidine derivatives fused with a 5-membered hetero ring having a non-peptidic GnRH antagonistic activity are described. However, there are no specific description about compounds other than that having a sulfonamide or amide group, and there are no specific description about pharmacokinetics in blood by oral administration.
As compounds having a pyrimidine ring fused with a 5-membered hetero ring, in addition to the above, various compounds are illustrated as serine protease inhibitors in Patent reference 4, blood coagulation factor Xa inhibitors in Patent reference 5 and herbicides in Patent reference 6, respectively. However, in any of these references, there are no descriptions or suggestion about that that a compound having a pyrimidine ring fused with a 5-membered hetero ring of the present invention has a GnRH antagonistic activity.
Non-patent reference 1: Hyojun Seirigaku (Standard Physiology), Edition 5, Igakusyoin, pp. 882-891.
Non-patent reference 2: Sanka to Fujinka (Obstetrics and Gynecology), 2004, Vol. 71, No. 3, pp. 280-285 and 301-307.
Patent reference 1: International publication No. WO1996/24597 pamphlet.
Patent reference 2: International publication No. WO2005/019188 pamphlet.
Patent reference 3: International publication No. WO2006/083005 pamphlet.
Patent reference 4: U.S. patent application publication No. 2003/0004167 description.
Patent reference 5: International publication No. WO00/39131 pamphlet.
Patent reference 6: Japanese patent publication No. Tokuhyo-Hei6-510992 (JP H06-510992 T) pamphlet.